Pain is a serious social and economic problem. It is calculated that more than 2 million persons are disabled every day due to suffering from temporary or chronic painful sensations. Clear examples are algesia experienced by patients with cancer, headache, arthritis, burns, injured patients and those surgically operated. Despite the severity of the problem, the pharmacological arsenal for controlling, preventing and/or reducing its symptoms and progress is surprisingly limited, partly due to the lack of specific target therapies.
Pain sensation begins when the peripheral terminals of a group of sensory neurons, known as nociceptor neurons, are activated by harmful chemical, mechanical or thermal stimuli (1, 2) [see the section relating to the LITERATURE]. Nociceptor neurons transmit the information about the tissue damage to the centers processing the pain sensation in the spinal cord and the brain.
Although the biological mechanisms necessary for pain transmission are not clearly established, it has been shown that the inflammation mediator compounds such as, for example, the neuronal growth factor and bradykinin, sensitize nociceptors decreasing their response threshold to harmful chemical, thermal and mechanical stimuli. The sensitization process seems to be mediated by the activation of intracellular signaling pathways leading to the modulation of the membrane receptors responsible for the integration of harmful stimuli. For example, it has been described that ion channels present on the nociceptor surface such as vanilloid receptor I, sodium channels, ionotropic glutamate receptors and purinergic receptors are actively modulated by pro-algesic agents. Accordingly, a strategy to reduce peripheral pain transmission and sensation is to act by reducing the pro-algesic sensitization of the nociceptors by means of developing chemical compounds which specifically interact on excitatory mechanisms and/or molecules and increase the response thresholds of the nociceptors.
Despite the progress carried out in the last years, specific analgesic compounds decreasing the pro-algesic sensitization of the nociceptors and therefore, aiding to alleviate painful sensations of the inflammatory process, had yet not been developed. The effort carried out up to date has largely consisted on developing opioids recognizing the opioid receptors of the central nervous system (1, 2). Although strong analgesics, these molecules show important side effects, such as addiction, tolerance, cognitive anomalies, etc., which limit their clinical use (3, 4). Likewise, a great investment has been carried out in the development of non-steroidal anti-inflammatory compounds. Although effective in the treatment of pain, these molecules have limitations, side effects and toxicology hindering their use, especially in chronic inflammatory pain. An important effort to develop competitive and non-competitive glutamate and/or glycine [a co-agonist participating in the activation of the N-methyl-D-aspartate activated glutamate receptor (NMDA)] antagonists has also been carried out. These inhibitors have been shown to be effective and powerful mitigating the pain sensation, but have shown a limited clinical utility again due to the cognitive-type side effects they show (5).
Therefore, there is still a need for searching for products capable to reduce and/or treat the peripheral pain sensation, overcoming the previously mentioned drawbacks.